Abstract:NLRP3 inflammasome plays an important role in innate immune system through recognizing pathogenic microorganisms and danger-associated molecules. Deubiquitination of NLRP3 has been shown to be essential for its activation, yet the functions of Ubc13, the K63-linked specific ubiquitin-conjugating enzyme E2, in NLRP3 inflammasome activation are not known. In this study, we found that in mouse macrophages, Ubc13 knockdown or knockout dramatically impaired NLRP3 inflammasome activation. Catalytic activity is requi… Show more
“…Recently, Ubc13 was also shown to associate with NLRP3 , catalyze K63-linked ubiquitination of NLRP3 and activate the inflammasome [ 64 ] ( Figure 2 , Figure 3 ). Upon stimulation with LPS and ATP, BMDMs from Ubc13 deltaMye mice (which specifically lack Ubc13 in myeloid cells; Ubc13 +/– ) showed diminished secretion of IL-1β and impaired caspase-1 maturation compared with WT ( Ubc13 +/+ ) controls [ 64 ]. Endogenous Ubc13 interacted with NLRP3 in BMDMs, correlating with inflammasome activation, NLRP3 was K63-ubiquitinated in the presence of WT Ubc13 but not mutant Ubc13C87A [ 64 ].…”
Section: K63 Ubiquitination In Immune Signalingmentioning
confidence: 99%
“…Upon stimulation with LPS and ATP, BMDMs from Ubc13 deltaMye mice (which specifically lack Ubc13 in myeloid cells; Ubc13 +/– ) showed diminished secretion of IL-1β and impaired caspase-1 maturation compared with WT ( Ubc13 +/+ ) controls [ 64 ]. Endogenous Ubc13 interacted with NLRP3 in BMDMs, correlating with inflammasome activation, NLRP3 was K63-ubiquitinated in the presence of WT Ubc13 but not mutant Ubc13C87A [ 64 ]. Figure 3 Ubiquitination signaling pathways in innate and adaptive immunity.…”
Section: K63 Ubiquitination In Immune Signalingmentioning
Ubc13-catalyzed K63 ubiquitination is a major control point for immune signaling. Recent evidence has shown that the control of multiple immune functions, including chronic inflammation, pathogen responses, lymphocyte activation, and regulatory signaling, is altered by K63 ubiquitination. In this review, we detail the novel cellular sensors that are dependent on K63 ubiquitination for their function in the immune signaling network. Many pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can target K63 ubiquitination to inhibit pathogen immune responses; we describe novel details of the pathways involved and summarize recent clinically relevant SARS-CoV-2-specific responses. We also discuss recent evidence that regulatory T cell (Treg) versus T helper (T
H
) 1 and T
H
17 cell subset regulation might involve K63 ubiquitination. Knowledge gaps that merit future investigation and clinically relevant pathways are also addressed.
“…Recently, Ubc13 was also shown to associate with NLRP3 , catalyze K63-linked ubiquitination of NLRP3 and activate the inflammasome [ 64 ] ( Figure 2 , Figure 3 ). Upon stimulation with LPS and ATP, BMDMs from Ubc13 deltaMye mice (which specifically lack Ubc13 in myeloid cells; Ubc13 +/– ) showed diminished secretion of IL-1β and impaired caspase-1 maturation compared with WT ( Ubc13 +/+ ) controls [ 64 ]. Endogenous Ubc13 interacted with NLRP3 in BMDMs, correlating with inflammasome activation, NLRP3 was K63-ubiquitinated in the presence of WT Ubc13 but not mutant Ubc13C87A [ 64 ].…”
Section: K63 Ubiquitination In Immune Signalingmentioning
confidence: 99%
“…Upon stimulation with LPS and ATP, BMDMs from Ubc13 deltaMye mice (which specifically lack Ubc13 in myeloid cells; Ubc13 +/– ) showed diminished secretion of IL-1β and impaired caspase-1 maturation compared with WT ( Ubc13 +/+ ) controls [ 64 ]. Endogenous Ubc13 interacted with NLRP3 in BMDMs, correlating with inflammasome activation, NLRP3 was K63-ubiquitinated in the presence of WT Ubc13 but not mutant Ubc13C87A [ 64 ]. Figure 3 Ubiquitination signaling pathways in innate and adaptive immunity.…”
Section: K63 Ubiquitination In Immune Signalingmentioning
Ubc13-catalyzed K63 ubiquitination is a major control point for immune signaling. Recent evidence has shown that the control of multiple immune functions, including chronic inflammation, pathogen responses, lymphocyte activation, and regulatory signaling, is altered by K63 ubiquitination. In this review, we detail the novel cellular sensors that are dependent on K63 ubiquitination for their function in the immune signaling network. Many pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can target K63 ubiquitination to inhibit pathogen immune responses; we describe novel details of the pathways involved and summarize recent clinically relevant SARS-CoV-2-specific responses. We also discuss recent evidence that regulatory T cell (Treg) versus T helper (T
H
) 1 and T
H
17 cell subset regulation might involve K63 ubiquitination. Knowledge gaps that merit future investigation and clinically relevant pathways are also addressed.
“…Additionally, Ubc13 transduces the NF-κB signal by interacting with TNF receptor-associated factor 6 (TRAF6) [99]. A recent study found that Ubc13 acts as a positive regulator for NLRP3 inflammasome activation, as Ubc13 deficiency significantly reduced NLRP3 inflammasome activation [100]. The study also revealed that Ubc13 interacts with NLRP3 to induce K63-linked polyubiquitination at K565 and K687 sites.…”
In response to diverse pathogenic and danger signals, the cytosolic activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing (3)) inflammasome complex is a critical event in the maturation and release of some inflammatory cytokines in the state of an inflammatory response. After activation of the NLRP3 inflammasome, a series of cellular events occurs, including caspase 1-mediated proteolytic cleavage and maturation of the IL-1β and IL-18, followed by pyroptotic cell death. Therefore, the NLRP3 inflammasome has become a prime target for the resolution of many inflammatory disorders. Since NLRP3 inflammasome activation can be triggered by a wide range of stimuli and the activation process occurs in a complex, it is difficult to target the NLRP3 inflammasome. During the activation process, various post-translational modifications (PTM) of the NLRP3 protein are required to form a complex with other components. The regulation of ubiquitination and deubiquitination of NLRP3 has emerged as a potential therapeutic target for NLRP3 inflammasome-associated inflammatory disorders. In this review, we discuss the ubiquitination and deubiquitination system for NLRP3 inflammasome activation and the inhibitors that can be used as potential therapeutic agents to modulate the activation of the NLRP3 inflammasome.
“…Multiple E3 negative regulators that affect NLRP3 levels or activation have been identified including FBXL2 (Han et al, 2015), PARKIN (Kang et al, 2016), and TRIM31 (Song et al, 2016), which provide a signal for proteasomal degradation, MARCH7 (Yan et al, 2015), which provides a signal for degradation by autophagy, and ARIH2 (Kawashima et al, 2017) and CUL1 (Wan et al, 2019), which bind and ubiquitinate NLRP3 to maintain its inactive state. Positive regulation of NLRP3 by the ubiquitin system has been observed with the interplay of numerous E3 enzymes including PELI2 (Humphries et al, 2018), TRAF6 (Xing et al, 2017), and TRIM33 (Weng et al, 2014), the E2 enzyme UBC13 (Ni et al, 2021), as well as the deubiquitinating enzymes BRCC3/ABRO1 (Py et al, 2013;Ren et al, 2019), USP7 and USP47 (Lopez-Castejon et al, 2013), and UCHL5 (Kummari et al, 2015). Negative regulation of the NLRP3 and AIM2 inflammasomes by ubiquitination of ASC promoting proteasomal degradation has also been shown by the TRAF6 E3 enzyme (Chiu et al, 2016) which, interestingly, has been shown to be a positive regulator of NLRP3.…”
Section: Ubiquitination and Deubiquitinationmentioning
Two key pathological hallmarks of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are the accumulation of misfolded protein aggregates and the chronic progressive neuroinflammation that they trigger. Numerous original research and reviews have provided a comprehensive understanding of how aggregated proteins (amyloid β, pathological tau, and α-synuclein) contribute to the disease, including driving sterile inflammation, in part, through the aggregation of multi-protein inflammasome complexes and the ASC speck [composed of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), Apoptosis-associated speck-like protein containing a C-terminal caspase activation and recruitment domain (ASC), and inflammatory caspase-1] involved in innate immunity. Here, we provide a unique perspective on the crosstalk between the aggregation-prone proteins involved in AD/PD and the multi-protein inflammasome complex/ASC speck that fuels feed-forward exacerbation of each other, driving neurodegeneration. Failed turnover of protein aggregates (both AD/PD related aggregates and the ASC speck) by protein degradation pathways, prionoid propagation of inflammation by the ASC speck, cross-seeding of protein aggregation by the ASC speck, and pro-aggregatory cleavage of proteins by caspase-1 are some of the mechanisms that exacerbate disease progression. We also review studies that provide this causal framework and highlight how the ASC speck serves as a platform for the propagation and spreading of inflammation and protein aggregation that drives AD and PD.
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